Molecular and cellular biology of pre-malignancy in the gastrointestinal tract

Important pathogenic alterations within established cancers are acquired during the premalignant stage. These genetic alterations can be grouped into specific neoplastic pathways that differ within and between anatomical sites. By understanding the mechanisms that determine the initiation and progression of each pathway, it will be possible to develop novel approaches to the diagnosis, prevention and treatment of cancer. This chapter outlines the principles underlying the molecular characterization of pre-malignant lesions, taking colorectal neoplasia as the main model.

Cigarette smoking and risk of epithelial ovarian cancer (Australia)

Objectives: We studied the association between cigarette smoking and ovarian cancer in a population-based case-control study. Methods: A total of 794 women with histologically confirmed epithelial ovarian cancer who were aged 18-79 years and resident in one of three Australian states were interviewed, together with 855 controls aged 18-79 years selected at random from the electoral roll from the same states. Information was obtained about cigarette smoking and other factors including age, parity, oral contraceptive use, and reproductive factors. We estimated the relative risk of ovarian cancer associated with cigarette smoking, accounting for histologic type, using multivariable logistic regression to adjust for confounding factors. Results: Women who had ever smoked cigarettes were more likely to develop ovarian cancer than women who had never smoked (adjusted odds ratio (OR) = 1.5; 95% confidence interval (CI) = 1.2-1.9). Risk was greater for ovarian cancers of borderline malignancy (OR = 2.4; 95% CI = 1.4-4.1) than for invasive tumors (OR = 1.7; 95% CI = 1.2-2.4) and the histologic subtype most strongly associated overall was the mucinous subtype among both current smokers (OR = 3.2; 95% CI = 1.8-5.7) and past smokers (OR = 2.3; 95% CI = 1.3-3.9). Conclusions: These data extend recent findings and suggest that cigarette smoking is a risk factor for ovarian cancer, especially mucinous and borderline mucinous types. From a public health viewpoint, this is one of the few reports of a potentially avoidable risk factor for ovarian cancer.

Pharmacokinetics and pharmacodynamics of melphalan in isolated limb infusion for recurrent localized limb malignancy

Isolated limb infusion (ILI) is an attractive, less complex alternative to Isolated limb perfusion (ILP). It has a lower morbidity in treating localized recurrences and in transit metastases of the limb for tumours such as melanoma, Merkel cell tumour and Kaposi's sarcoma, allowing administration of high concentrations of cytotoxic agent to the affected limb under hypoxic conditions. Melphalan is the preferred cytotoxic agent for the treatment of melanoma by ILP or ILI. We report pharmacokinetic data from 12 patients treated by ILI for tumours of the limb in Brisbane. The kinetics of drug distribution in the limb was calculated using a two-compartment vascular model, where both tissue and infusate act as well-stirred compartments. Analysis of melphalan concentrations in the perfusate during ILI showed good agreement between the values measured and the concentrations predicted by the model. Recirculation and wash-out flow rates, tissue concentrations and the permeability surface area product (PS) were calculated. Correlations between the PS value and the drug concentrations In the perfusate and tissue were supported by the results. These data contribute to a better understanding of the distribution of melphalan during ILI in the limb, and offer the opportunity to optimize the drug regimen for patients undergoing ILI. (C) 2001 Lippincott Williams & Wilkins.

Urine D-arabinitol/L-arabinitol ratio in diagnosing Candida infection in patients with haematological malignancy and HIV infection

Adult patients with hematologic malignancies along with HIV infected patients were prospectively studied to determine the performance of urine D-arabinitol/L-arabinitol (DA/LA) ratio in diagnosing invasive candidiasis. Ten evaluable febrile neutropenic patients had proven invasive candidiasis and elevated DA/LA ratios were found in 5. Invasive candidiasis with normal DA/LA ratios was most frequently due to Candida krusei infection. This Candida species is a non-producer of arabinitol. Only 4 of 81 febrile neutropenic patients given either antifungal prophylaxis or empiric antifungal treatment had elevated DA/LA ratios. Only 1 of 15 HIV positive patients with either oropharyngeal or esophageal candidiasis had elevated DA/LA ratios. Widespread use of fluconazole prophylaxis in bone marrow transplantation patients at the study hospital has led to an increased prevalence of C. krusei infection. This is the likely reason for the low sensitivity of the test in proven and suspected invasive Candida infections reported here. (C) 2002 Elsevier Science Inc. All rights reserved.

Cryptococcus gattii fungemia: report of a case with lung and brain lesions mimicking radiological features of malignancy

A 64-year-old apparently immunocompetent white man developed lung and brain lesions of disseminated cryptococcosis. The radiologic features mimicked those of lung cancer metastatic to the central nervous system. C. gattii was recovered from cultures of bronchoalveolar lavage fluid, brain biopsy, and blood. The same fungus was recovered from pulmonary and brain specimens at autopsy. Serum and cerebrospinal fluid cryptococcal antigen tests were diagnostic in our case and should be included in the diagnostic evaluation of unexplained pulmonary and cerebral lesions. A literature search showed few reports of fungemia by this species of Cryptococcus, contrasting to C. neoformans.

Diabetic Mastopathy: a Case Report

Diabetic mastopathy (DMP) is an uncommon collection of clinical, radiological, and histological features, classically described in premenopausal women with long-term insulin-dependent diabetes mellitus. This entity can mimic breast carcinoma, but, in the appropriate clinical and imaging setting, the diagnosis can be made by core biopsy, avoiding unnecessary surgeries. We report the case of a 34-year-old female, with a 12-year history of type 1 diabetes, who presented with bilateral breast lumps. Mammography, ultrasonography, and magnetic resonance imaging could not exclude the suspicion of malignancy, and a core biopsy was performed showing the typical histologic features of DMP. The literature is briefly reviewed.

Adenocarcinoma of the Ileum: A Rare and Challenging Entity

INTRODUCTION: Primary small bowel malignancy is unusual and accounts for 1-3% of all gastrointestinal tract neoplasms. Adenocarcinoma is one of the most common histologic types, but its frequency decreases with more distal locations. Its clinical presentation is nonspecific and is usually associated with advanced disease, which contributes to delayed diagnosis. PRESENTATION OF CASE: A 66-year-old woman was admitted to the hospital with a 6-day history of progressively worsening abdominal pain localized in the right lower quadrant, nausea, and vomiting. Investigation revealed an inflammatory appendiceal tumor. The patient underwent surgery and an unexpected tumor involving the distal ileal segment and ileocecal appendix was found. Right radical hemicolectomy with en bloc resection of the distal ileum was performed. Histopathological examination revealed adenocarcinoma of the ileum. DISCUSSION: This rare entity is associated with a nonspecific clinical presentation that contributes to delayed diagnosis and treatment, and consequently to a worse prognosis. Approximately half of the cases are only diagnosed at surgery. Primary treatment consists of wide resection with locoregional lymphadenectomy. The role of adjuvant chemotherapy has yet to be determined. CONCLUSION: This case demonstrates an unusual condition characterized by late and challenging diagnosis. We highlight the importance of an earlier diagnosis and optimal treatment for improved patient outcomes.

Fulminant hepatitis with microvesicular steatosis (a histologic comparison of cases occurring in Brazil - Labrea hepatitis - and in central Africa - Bangui hepatitis)

A similar histopathologic picture of fatal hepatitis associated with widespread acute fatty changes in hepatocytes and single-cell necrosis was seen in epidemic cases occurring in two distinct equatorial areas having high prevalences of HBV and HDV infections. The cases were previously considered to be two different entities; Labrea hepatitis in Brazil, and Bangui hepatitis in the Central African Republic. However, the histopathologic findings suggest that they are pathogenetically and etiologically related to HBVand HDV infections, probably modified by some as yet unknown factor (s) present in equatorial forest zones.

Role of colonoscopy in colorectal cancer

Colorectal cancer (CRC) represents the third most common malignancy throughout the world. Little or no improvement in survival has been effectively achieved in the last 50 years. Extensive epidemiological and genetic data are able to identify more precisely definite risk-groups so screening and early diagnosis can be more frequently accomplished. CRC is best detected by colonoscopy, which allows sampling for histologic diagnosis. Colonoscopy is the gold standard for detection of small and premalignant lesions, although it is not cost-effective for screening average-risk population. Colonoscopic polypectomy and mucosal resection constitute curative treatment for selective cases of invasive CRC. Similarly, alternative trans-colonoscopic treatment can be offered for adequate palliation, thus avoiding surgery.

Tissue hyaluronan expression, as reflected in the sputum of lung cancer patients, is an indicator of malignancy

Hyaluronan (HA) shows promise for detecting cancerous change in pleural effusion and urine. However, there is uncertainty about the localization of HA in tumor tissue and its relationship with different histological types and other components of the extracellular matrix, such as angiogenesis. We evaluated the association between HA and degree of malignancy through expression in lung tumor tissue and sputum. Tumoral tissue had significantly increased HA compared to normal tissue. Strong HA staining intensity associated with cancer cells was significant in squamous cell carcinoma compared to adenocarcinoma and large cell carcinoma. A significant direct association was found between tumors with a high percentage of HA and MVD (microvessel density) in tumoral stroma. Similarly significant was the direct association between N1 tumors and high levels of HA in cancer cells. Cox multivariate analysis showed significant association between better survival and low HA. HA increased in sputum from lung cancer patients compared to cancer-free and healthy volunteers and a significant correlation was found between HA in sputum and HA in cancer tissue. Localization of HA in tumor tissue was related to malignancy and reflected in sputum, making this an emerging factor for an important diagnostic procedure in patients suspected to have lung cancer. Further study in additional patients in a randomized prospective trial is required to finalize these results and to validate our quantitative assessment of HA, as well as to couple it to gold standard sputum cytology.

Morphogenesis of the ureterovesical junction:a histologic and microanatomic study in the rat.

OBJECTIVES: To investigate the development of the ureterovesical junction in rats. METHODS: A total of 110 albino rats (50 prenatal and 60 newborn) with a gestation of 21 days were studied at the age of 17 days after conception until 5 days after birth. The lower urinary tract was microdissected. Microphotography (110 animals), histologic examination (44 animals), and scanning electron microscopy (66 animals) of the ureterovesical junction were performed. Urea and creatinine from the amniotic fluid of 20 fetuses and from the urine of 10 neonates were measured. RESULTS: At day 17 after conception, separate penetration of the mesonephric duct and ureter into the wall of the urogenital sinus was observed. Continuity between the lumen of the ureter and the urogenital sinus was established on day 19 after conception. The straight passage of the intramural ureter into the urogenital sinus at day 17 after conception changed to the definitive L-shape with a vertical entry into the bladder on day 5 after birth. In the distal ureter, the change of the mesenchymal tissue into immature smooth muscle was first observed at birth, and the muscle became mature on the fifth postnatal day. At birth, Waldeyer's sheath was recognized. The creatinine and urea levels were stable prenatally (average 22.4 micromol/L and 6.88 mmol/L, respectively) and rose significantly postnatally (average 133 micromol/L and 32.65 mmol/L, respectively). CONCLUSIONS: The attachment of the ureter to the urogenital sinus and later to the bladder, the modification of its passage, and its mobility within Waldeyer's sheath may be essential in preventing vesicoureteral reflux. The production of urine and its flow does not seem to be the trigger of ureteral smooth muscle formation.

Comment évaluer le risque oncologique d'un patient souffrant de dermatomyosite [Can we predict the risk of malignancy associated with dermatomyositis?]

Dermatomyositis (DM) and polymyositis (PM) are idiopathic inflammatory muscle diseases which remain a therapeutic challenge. The association between DM and malignancy is relatively well established while this relationship is weaker with PM. The clinical management and research for an occult malignancy as well as the follow-up of patients with DM or PM is a matter of debate. Herein we report a case of DM who, despite an extensive clinical, radiological and biological work-up developed an occult ovarian cancer 12 months after the initial diagnosis. This case report was used as support to review the actual expert recommendations for the search of an occult malignancy in presence of DM or PM.

Parasite and egg burden, hepatic collagen and histologic pattern of liver granulomas in selection III high and low antibody responder mice infected with Schistosoma mansoni

Selection III mice have particular immunological characteristics: they are high (H III) or low (L III) antibody producer animals, yet both lines display similar T cell responses and macrophage activities. We submittedthese mice to infection with Schistosoma mansoni to assess in vivo parasite and egg burden, hepatic collagen and cellular composition of granulomas in both lines. Titration of anti-Schistosoma IgG by ELISA showed remarkably higher values inH III line, at both studied periods (8th and 12th weeks post-infection). Nevertheless, the number of adult worms recovered from the portal system was similar inboth lines, being not associated with anti-Schistosoma antibody levels. There isan increase in hepatic collagen from the 8th to the 12th weeks post-infection, which is paralleled by an increase in the number of eggs in the liver. This association apparently occurs at the same radio in H III and L III animals. The most important difference found between the two lines was the outstanding contrast interms of volume and eosinophil counts in the granulomas, with lesions from H IIImice clearly being larger and containing more of these cells than LIII lesions.